通过叔丁酯保护羧基
相对而言叔丁酯是位阻较大的酯,大位阻酯的特性就是对于碱的稳定性较高,一般都是利用酸水解脱保护。下面介绍的叔丁酯的保护方法中,对于其他位阻较大的酯的合成也可借鉴。1-和2-金刚烷酯已经用于氨基酸的保护【1-AdOH, 甲苯,硫酸二甲酯,催化量TsOH,70-80%收率,Synthesis,1355(1996) 】。
上保护:
一、异丁烯,浓硫酸,乙醚,室温,2-24h,50-60%收率,此方法可以用于脂肪酸、氨基酸【J. Am. Chem. Soc., 82, 3359(1960) / Synthesis, 786(1988)】和青霉素【J. Med. Chem., 9, 444(1966)】类叔丁酯的制备。
二、异丁烯,二氯甲烷,H3PO4(P2O5), 三氟化硼乙醚,-78℃,2h,0℃,24h。【J. Org. Chem.,51, 1253(1986)】
三、草酰氯,苯,DMF, 7-10℃,45min;叔丁醇,三乙胺,二氯甲烷,0℃,3h,75%收率。【J. Org. Chem.,35, 2429(1970)】
四、叔丁醇,吡啶,(Me2N)ClC=N+Me2Cl-,77%收率,此方法同样可以合成其他类型的酯。【Chem. Lett., 1891(1982)】
五、2,4,6-三氯苯甲酰氯,三乙胺,THF;叔丁醇,DMAP,苯,室温,20min,90%收率。【Bull. Chem. Soc. Jpn., 52, 1989(1979)】
六、CDI,叔丁醇,DBU,54-91%收率。【Synthesis, 833(1982)】
七、叔丁醇,EDCI,DMAP,二氯甲烷,88%收率,Cbz-脯氨酸保护时无外消旋发生。【J. Org. Chem.,47, 1962(1982)】
八、i-PrN=C(Ot-Bu)NH-i-Pr,甲苯,60℃,4h,90%收率。【Tetrahedron Lett., 34, 975(1993)】
九、(BOC)2O, 叔丁醇,THF,DMAP,99%收率。此方法还可以用于合成烯丙基,甲基,乙基,和苄基酯。【Synthesis, 1063(1994)】
十、当酸的α位有吸电子基团的时候,可以应用此方法:叔丁醇,DCC,60-100%产率,反应中通过生成烯酮中间体得以进行。此方法可以用于合成各种大位阻的酯基。【Org. Lett., 3, 3733(2001)】
十一、DCC,DMAP, 叔丁醇。【Organic Syntheses, Coll. Vol. 7, p.93 (1990); Vol. 63, p.183 (1985)】
A 500-mL, one-necked flask equipped with a calcium chloride drying tube was
charged with 28.83 g (0.20 mol) of monoethyl fumarate, 200 mL of dry dichloromethane, 44.47 g (0.60 mol) of tert-butyl alcohol, and 2.00 g (0.16 mol) of 4-dimethylaminopyridine. The solution was stirred and cooled in an ice bath to 0°C while 45.59 g (0.22 mol) of dicyclohexylcarbodiimide was added over a 5-min period. After a further 5 min at 0°C the ice bath was removed and the dark-brown reaction mixture was stirred for 3 h at room temperature. The dicyclohexylurea that has precipitated was removed by filtration through a fritted Büchner funnel (G3), and the filtrate was washed with two 50-mL portions of 0.5 N hydrochloric acid and two 50mL portions of saturated sodium bicarbonate solution. During this procedure some additional dicyclohexylurea was precipitated, which was removed by filtration of both layers to facilitate their separation. The organic solution was dried over anhydrous sodium sulfate and concentrated with a rotary evaporator. The concentrate was distilled under reduced pressure, affording after a small forerun, 30.5–32.5 (76–81%)
of tert-butyl ethyl fumarate, bp 105–107°C (12 mm)。
去保护
叔丁酯对氨,肼和温和条件的碱水解稳定;可以通过中等强度的酸性水解去保护,注意必须去除生成的叔丁基正离子,以避免副反应的发生。
一、甲酸,室温,3h。【J. Org. Chem., 42, 3972(1977)】
二、TFA,二氯甲烷,室温,1h。加入三乙基硅烷作为正离子清除剂,效果明显,可以提高收率。【Tetrahedron Lett., 33, 5441(1992)】
三、TFA,苯甲硫醚,93%收率。在此例中苯甲硫醚起到至关重要的作用。【Org. Lett., 1, 79(1999)】
另外苯酚和1,3-二甲氧基苯也常被用作正离子清除剂,对于一些富电子的底物的水解反应中,加入正离子清除剂非常重要。
四、乙酸,HBr,10℃,10min,70%收率,氨基酸上的邻苯二甲酰或三氟乙酰基对此条件稳定,Cbz和Boc被去保护。【J. Am. Chem. Soc., 82, 3359(1960)】
五、HCl,AcOH,二氯甲烷,5℃,2h。叔丁醚和Fmoc基团不受影响。【Tetrahedron Lett., 38, 5069(1997)】
六、硫酸,二氯甲烷,室温,6h,89-98%收率。此条件可以去保护Boc和金刚烷酯。【Tetrahedron Lett., 46, 2075(2005)】
七、硝酸,二氯甲烷,0℃,92-99%收率。此条件比常用的TFA的反应速度更快。【Tetrahedron Lett., 39, 9255(1998)】
八、KOH,18-冠-6,甲苯,100℃,5h,94%收率。此条件用于芳香叔丁酯的去保护,但此条件对于多官能团底物太剧烈,不适用。【J. Am. Chem. Soc., 89, 7017(1967)】
九、50% aq. NaOH,苄基三乙基氯化铵,二氯甲烷,90-98%收率。【Tetrahedron Lett., 44, 2359(2003)】
十、叔丁醇钾(2eq),THF,0℃,35-100%收率。【Tetrahedron Lett., 41, 655(2000)】
十一、NaH, DMF,室温2-24h或70℃,60-87%收率,此条件是通过DMF分解得到的MeNNa起作用的。【Synlett,1107(2002)】
十二、TBSOTf,2,6-lutidine,二氯甲烷,室温,93%收率,此条件是将叔丁酯转化为硅酯。【J. Am. Chem. Soc., 119, 10073(1997)】
十三、四氯化钛,二氯甲烷,-10到0℃,54-91收率,此条件常用于头孢素叔丁酯去保护。【Tetrahedron Lett., 39, 1625(1998)】
编译自: Protective groups in organic synthesis (Wuts & Greene,4th Ed), P: 582-588.